Hepatic mitochondrial dysfunction is a feature of Glycogen Storage Disease Type Ia (GSDIa)
Hepatic mitochondrial dysfunction is a feature of Glycogen Storage Disease Type Ia (GSDIa)
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DOI：
10.1038/srep44408
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发表时间：
2017-03-20
影响因子：
4.6
通讯作者：
Yen, Paul M.
中科院分区：
文献类型：
--
作者：
Farah, Benjamin L.;Sinha, Rohit A.;Yen, Paul M.
Ia型糖原储存病(GSDIa，von Gierke病)是最常见的糖原储存障碍。它是由葡萄糖-6-磷酸酶缺乏引起的，葡萄糖-6-磷酸酶是催化糖异生和糖原分解的最后一步的酶。临床上，GSDIa以空腹低血糖、肝糖原和甘油三酯过度积聚为特征。后者导致脂肪性肝炎、肝硬变，以及肝腺瘤和癌的形成。目前，人们对GSDIa中各种细胞器的功能及其对代谢的影响知之甚少。因此，我们研究了线粒体在细胞培养和GSDIa小鼠模型中的功能。我们发现，在这些模型系统中，氧化磷酸化和TCA循环代谢产物的损害，以及线粒体膜电位的降低和线粒体超微结构的紊乱。线粒体含量也下降，可能是由于线粒体生物合成减少所致。这些有害的影响最终导致线粒体凋亡途径的激活。综上所述，我们的结果证实了线粒体功能障碍在GSDIa发病机制中的作用，并确定了治疗该疾病的新的潜在靶点。他们还为碳水化合物超负荷对线粒体功能在其他肝病中的作用提供了新的见解，例如非酒精性脂肪肝。
Glycogen storage disease type Ia (GSDIa, von Gierke disease) is the most common glycogen storage disorder. It is caused by the deficiency of glucose-6-phosphatase, an enzyme which catalyses the final step of gluconeogenesis and glycogenolysis. Clinically, GSDIa is characterized by fasting hypoglycaemia and hepatic glycogen and triglyceride overaccumulation. The latter leads to steatohepatitis, cirrhosis, and the formation of hepatic adenomas and carcinomas. Currently, little is known about the function of various organelles and their impact on metabolism in GSDIa. Accordingly, we investigated mitochondrial function in cell culture and mouse models of GSDIa. We found impairments in oxidative phosphorylation and changes in TCA cycle metabolites, as well as decreased mitochondrial membrane potential and deranged mitochondrial ultra-structure in these model systems. Mitochondrial content also was decreased, likely secondary to decreased mitochondrial biogenesis. These deleterious effects culminated in the activation of the mitochondrial apoptosis pathway. Taken together, our results demonstrate a role for mitochondrial dysfunction in the pathogenesis of GSDIa, and identify a new potential target for the treatment of this disease. They also provide new insight into the role of carbohydrate overload on mitochondrial function in other hepatic diseases, such as non-alcoholic fatty liver disease.